FR2540491A1 - NOVEL NITROSOUREES, PROCESS FOR THE PREPARATION THEREOF AND THERAPEUTIC APPLICATION THEREOF - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW NITROSOUREES, AND THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS. THESE ARE COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) OF SERIES L, D, DL, ALLO AND THREO, IN WHICH: A REPRESENTS THE FRAGMENT OF AN AMINO ACID OF FORMULA HN (R) -A-COOH , OR R REPRESENTS A HYDROGEN ATOM, AN ORGANIC RADICAL, IN PARTICULAR AN ALKYL RADICAL, OR SHAPED WITH THE NITROGEN ATOM AND A HETEROCYCLE; Y REPRESENTS A RADICAL NITROSOUREE OF FORMULA: (CF DRAWING IN BOPI) X REPRESENTS A RADICAL NITROGEN MUSTARD OF FORMULA: (CF DRAWING IN BOPI) APPLICATION TO THE TREATMENT OF TUMORS.

Description

The present invention relates to novel nitrosoureas, their method of

preparation and their

therapeutic application.

  It is known that certain halo-alkyl-nitrosoureas, in particular certain 2-chloro-ethyl-nitrosoureas, constitute a class of compounds of particular interest because of their oncostatic activity on malignant tumors in animals and humans and that these compounds are useful for chemotherapy

cancer.

  Many efforts have been made to develop new compounds of this series that may have greater antineoplastic efficacy.

and / or lower toxicity.

  Thus, quite recently, new nitrosoureas derived from C-terminal free amino acids or amides have been proposed.

  showed interesting cytotoxic activity.

  The present invention relates to new nitrosoureas, derived from amino acids, which take advantage of the polyfunctional nature of the amino acids which, for the simplest, have at least two reactive sites: an amine function and an acid function. According to the invention, the amine function allows the grafting of a nitrosourea cytotoxic entity, whereas the acid function allows the

  grafting a mustard entity to nitrogen.

  The invention relates more particularly to these compounds of formula

Y N (R) -A-C 1 + X

  O -0 series L, D, DL, allo and threo, wherein 2540491 t A represents the fragment of an amino acid of formula HN (R) -A-COOH, where R represents a hydrogen atom, a organic radical, in particular an alkyl radical, or forms with the nitrogen atom and has a heterocycle; Y represents a nitrosourea radical of formula

O O

  C 1 -CH 2 -CH 2 -N-C or CH-N-C; and

NO NO

  X represents a nitrogen mustard radical of formula

  Cl-CH 2 -CH 2 -NH-, (Cl-CH 2 -CH 2) 2 N or (Cl-CH 2 -CH 2) 2 N-C 6 H 4 -NH-

  These compounds thus carry two recognized cytotoxic entities, namely at least one nitrosourea Y on the N-terminal side of the amino acid and at least one nitrogen mustard X on the C-terminal side. amino acid base has two acid functions (eg aspartic acid), the compound then has

  a nitrosourea and two mustard entities with nitrogen.

  In the case where the basic amino acid has two amine functions (lysine, for example), the compound then has two nitrosoureas and a mustard entity.

with nitrogen.

  It is therefore polyfunctional compounds

  which are fundamentally different from known monofunctional compounds

  nitrosourea grafted on an amino acid.

  A first group of compounds according to the invention corresponds to the formula Y ## STR1 ## in which: R 'is chosen from the radicals H, -CH 3 -CH 2 OH,

  -CH-OH, -CH (CH 3) 2, -CH 2 -CH 3, -CH 2 -CH (CH 3) 2 '

  CH 3 CH 2 CH 3 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -CH 2 -CH 2 -CONH 2, - (CH 2) n CO-XD - (CH 2) n -NH-Y,

  (CH 2) 3 NH-C-NH-Y O -CH 2 -CH 2 SH, -CH 2 -CH 2 -OH, - (CH 2) 2 CH-OH-CH 2 -NHY;

  NH n represents an integer of 1 to 7; and

  X and Y have the same meaning as above.

  This first group thus essentially comprises

  natural amino acids and their derivatives.

  A second group of compounds according to the invention corresponds to the formula 4 Y NH- (CH 2) n X (Ib) O in which n represents an integer from 1 to 7; and

  X and Y have the same meaning as above.

  This second group thus comprises non-natural amino acids since they can only be obtained by synthesis. A third group of compounds according to the invention corresponds to the formula R "(Ic) or Y (Id) YA-x wherein R represents an organic radical, in particular an alkyl radical, and

  X and Y have the same meaning as above.

  Among the preferred compounds of the invention, mention should be made of those for which A in formula I represents the fragment of an amino acid chosen from Ala, Ala, Asp, Asn, Gly, GABA, Ile, Leu, Lys, Met,

Phe, Pro, Trp and Tyr.

  The process for the preparation of the compounds of formula I can be represented by the following scheme: P N (R) -A-C O

P N (R) -A-C X

o 'O

H N N (R) -A-C X

O

Y N (-R) -A-C X

  The process of the invention comprises the following steps: A compound of formula PN (R) -AC 4 O Act (II) is reacted with the above meaning, P represents a grouping protector and Act an activating group, on the hydrochloride of the formula amine

HX (III)

  o X has the meaning above, to give a compound of formula

P N (R) -A X (IV)

  The compound of formula IV is then hydrogenated to give a compound of the formula ## STR2 ## The compound of formula V is then reacted with a nitrosocarbamate of formula y-O Act (VI).

  o Yet Act have the meaning above.

  In the above process, 2-chloroethyl-hitrosourea and methyl-nitrosourea were used as the nitrosourea species and 2-chloroethylamine, bis- (2-chloroethyl) as nitrogen mustard entities.

  amine and N-N-bis (2-chloroethyl) phenylene diamine.

  The N-protecting group P can be indifferent

  A benzyloxycarbonyl (Z) or tert-butyloxycarbonyl (Boc) group is used. In the case of sulfur-containing amino acids, it is preferred to use the Boc group. Activation is preferably carried out by an activated ester. a radical

  paranitrophenol or N-hydroxysuccinimide.

  The introduction of 2-chloroethyl-nitrosourea and methylnitrosourea is advantageously carried out from activated N (2-chloroethyl) -Nitrosocarbamates or activated N-methyl-N-nitrosocarbamate, respectively. In the above process, the reaction of the compound of formula II with the compound of formula III is carried out in the presence of an organic solvent, for example dimethylformamide (DMF). The solvent is then distilled off and the residue is taken up in the following manner: ethyl acetate and then the organic phase obtained is dried and concentrated

  and the residue obtained is recrystallized.

  The hydrogenation of the compound of formula IV is carried out in an organic solvent, for example in ethane, in the presence of palladium on charcoal, under normal pressure and at room temperature. The catalyst is then eliminated by filtration and then concentrated.

dry and dry the filtrate obtained.

  The compound of formula V thus obtained is dissolved

  in an organic solvent and the nitroso-

  Bamate of formula VI The reaction mixture is then left at ambient temperature and then concentrated under reduced pressure. The residue obtained is then chromatographed and the pure compound is recrystallized.

formula I thus obtained.

  The preparation of the nitrosoureas of the invention will now be described in more detail with the aid of the following nonlimiting examples:

Example 1

  General procedure for obtaining N-Erotected amino acid 2-chloroethylamine To an OC cooled solution of 2.32 g (0.02 mole) of 2-chloro-ethylamine hydrochloride and 3.45 ml (0.02 mol) of diisopropylethylamine in 30 ml of DMF, 0.01 mol of activated ester (paranitrophenol or N-hydroxysuccinimide) of a protected N-amino acid The reaction mixture is stirred

  overnight at room temperature.

  The solvent is then distilled under reduced pressure. The residue is dissolved in 200 ml of ethyl acetate. This solution is washed with 2 × 100 ml of a 10% aqueous solution of citric acid, 2 × 100 ml of water. 2 x 100 ml of a saturated aqueous solution of sodium bicarbonate, 2 x 100 O ml of water The organic phase is dried over sodium sulphate and concentrated

under reduced pressure.

  The residue obtained is, depending on the case, directly recrystallized or recrystallized after chromatography

on a silica column.

  By following this general procedure, we

  prepared the compounds of Examples 1 1 to 1 9 ci-

below:

Example 1 1.

  Nt-Butloxcarbon E 9 1-alanine 2-chloro-1-ethylamide From Nt-Butyloxycarbonyl-alanineo N-hydroxysuccinimide ester Recrystallization from dichloromethane / petroleum ether (1/1 ) Yield 65%

Mp = 25.87C

  Analysis: C 1 H 19 N 203 C (C, HN) TLC -: - R f = 0.40 (ethyl acetate)

Example 1 2

  N-carbobenzoxy-4-amino-2-acid 2-chloroethylamide

  butanoic starting from the N-hydroxysuccinimide ester of

  N-carbobenzoxy-4-aminobutanoic acid.

  Recrystallization from a mixture of ethyl acetate and petroleum ether (1/1) Yield 63%

F = 97.99 C

Analysis C 14 H 19 N 203 C 1 (C, HN)

Y 14 19 2 3 CHN

TLC: Rf = 0.35 (Ethyl acetate)

Example 1 3

  N-t-buty 1 oxycarbonyl-L-alanine-2-chloro-3-ethylamide From the para-nitrobenyl ester of N-t-butyloxycarbonyl-L-alanine The residue is chromatographed on a column

  of silica Eluent dichloromethane / ether 1/1.

  Recrystallization from a mixture of ether and light petroleum (1/3) Yield 76%

Mp 101-103 ° C

Analysis: Cl OH 19 N 203 C 1

(C HN)

  TLC Rf = 0.68 (Dichloromethane / Ethe r-2/1)

= 8.10 (C = 1, DM?)

D

Example 1 4

  N-carbobenzoxy-L isol eucine-2-chloro-4-ethylamide From the N-hydroxysuccinimide ester

N-carbobenzoxy-L-isoleucine.

Recrystallization in ethanol.

Yield 78%

M.p. = 175-177 C

CH analysis N O c (CH, N)

  TLC: Rf = 0.68 (ethyl acetate / dichloromethane)

  methane-1 / il (a) = + 3.50 (C 1, DM 2) D

Example 1

  N-carbobenzoxyl-leucine-2-chloro-3-ethylamide from the N-hydroxysuccinimide ester of

N-carbobenzoxy-L-leucine -

  Recrystallization from a mixture of ethyl acetate and petroleum ether (i / 5) Yield 91% F = 101 ° -103 ° C. Analysis C 161123 N 203 (C, H, N)

  TLC Rf 0.65 (ethyl acetate / dichloromethane)

  methane 1/1) (a) = 8.8 O <c = 2.5 DMF) D

Example 1 6

  N-t-Butyl 1 xycarbonyl-L-methionine-2-chloro-6-ethylnamide From the N-hydroxysuccinimide ester

  N-t-Butyloxycarbonyl-L-methionine.

  Obtained as an oil and used without

  additional purification for the next step.

Example 1 7

  N-tert-butyioxycarbonyl sarcosine (2-chloro-ethyl) -7-

  amide From the N-hydroxysuccinimide ester

  N-tert-butyloxycarbonyl sarcosine.

  Recrystallization in a mixture of ethyl acetate and hexane (1/1) Yield 80%

F = 119 C

Analysis = C 0 H 19 N 203 Cl (C, H, N)

19 2 3

TLC Rf: 0.41 (Ethyl acetate)

Example 1 8

  Na N -Dicarbobenzoxy-L-Lysine-2-chloro-8-ethylamide -1

1 _ _ __ _ __ __

  From the N-Hydroxysuccinimide ester

  Na, Ns -Dicarbobenzoxy-L-lysine.

  Recrystallization in a mixture of Acetate

and Hexane (1/1).

Yield 88%

M.p. 123-125 ° C .;

  Analysis C 24 H 30 N 305 C 1 (C, H, N) TLC: Rf = 0.52 (Ethyl acetate) () 20 = + 4.2 (c = 1 DMF) D

Example 1 9

  2-Dichloro-2-ethylamide of N-carbobenzoxy-L-

  To an O OC solution of 5.34 g (0.02 mol) of N-carbobenzoxy-Laspartic acid in 70 ml of DMF was successively added 9.28 g (0.08 mol) of hydrochloride.

  of 2-chloro-ethylamine, 13.8 ml (0.08 mole) of diisocyanate

  propylethylamine, and 8.24 g (0.04 mole) of N, N'-dicyclo

  hexylcarbodiimideo After 20 hours at room temperature, the N, N'-dicyclohexylurea formed is filtered, the filtrate is concentrated under reduced pressure and the residue is taken up in 200 ml of ethyl acetate. The solution obtained is then treated as

  described in the general method.

  The white crystals obtained are recrystallized

in isopropyl alcohol.

Yield 2.4 g or 31%

F = 174 1760 C

  Analysis: C 16 H 21 N 304 C 12 (C, H, N) TLC: Rf = 0.43 (dichloromethane / methanol 94/6) (a) = + 2.6 (C = 1, DMF) D

Example 2

  General operating procedures for obtaining 2-chloro

  substituted thyl_nitrosocarbamoyl amino-amides

or not).

  Process A (0.01 mole) of N-carbobenzoxy amino acid amide is hydrogenated in solution in 100 ml of ethane.

  10% palladium on carbon and one

  are equivalent to a 10% aqueous solution of hydrochloric acid

  drique, under normal pressure and at room temperature.

  When TLC reveals the absence of starting compound, the catalyst is removed by filtration on paper, the filtrate is concentrated to dryness under reduced pressure The residue is triturated in anhydrous ether until a powder is obtained is collected,

  washed with ether and dried in a desiccator.

  The N-deprotected derivative is then dissolved in 20 ml of DMF One equivalent (0.01 mole, 172 ml) of diethylamine DIEA is added cold, then 0.012 mole (3.98 g) of N-2- (chloroethyl ) 2,4,5-trichlorophenyl N-nitroso carbamate. The reaction mixture is left for 3 hours at room temperature, and then concentrated under reduced pressure. The residue is chromatographed on a silica column. The pure product obtained is recrystallized from silica gel.

appropriate solvent.

  The yield is calculated from the derivative

N-protected.

  Method B 0.01 mole of N-t-butyloxycarbonyl amino acid amide is dissolved in 20 ml of anhydrous trifluoroacetic acid in the presence of 2% thioanisole at room temperature. After 40 minutes, the solution is concentrated under reduced pressure; the residue is triturated in

  anhydrous ether until a powder is obtained.

  The rest of the operations are carried out as in method A.

  Following method A or method B,

  above, the following compounds are prepared.

254049 1

Example 2 1

  : 12-chloro-ethyl) N-nitrosocarbamoyl-alanine (2-chloroethyl)

  ethyl) -10-amide Obtained from the precursor of Example 11; Process B. Chromatography eluent: dichloromethane / acetate

of ethyl (3/1).

  Recrystallization in a mixture of ethyl acetate

and petroleum ether (1/1).

  Yield: 66% F = 84 85 C (dec) Analysis C 8 H 14 N 43 C 12 (CI H, N) TLC: Rf 0.58 (ethyl acetate) IR v = 1470 cm-1 (N-NO )

Example 2 2

  4-IN- (2-chloro-ethyl) -N-nitrosoureido-12-chloro-ethyl) -butanoyl-2-chloroethyl N-nitrosoureido Obtained from the precursor of Example 1 2 Method A

  Chromatography eluent: ethyl acetate.

  Recrystallization in a mixture of ether and hexane (1/1) o Yield: 79% F = 63 64 C (dec) Analysis: C 9 H 16 N 403 C 1 2 (C, H, N) TLC: Rf = 0, 45 (ethyl acetate) IR: = 1485 cm 1 (N-NO)

Example 2 3

  N: J 22 CH 12 OR 2 ethyl) N-nitrosoca rbamoyl -L-alanine 12-chloro-ethyl-12-amide Obtained from the precursor of Example 1 3 Method B Chromatographic eluent: dichloromethane / dichloromethane ethyl (9/1) Recrystallization from a mixture of dichloromethane and hexane (1/1) Yield z 60% F = 112 -11400 <dec) Analysis z C 8 H 14 NO c 2 (C, H, N) TLC: 0.43 (dichloromethane / ethyl acetate 2/1) IR = v = 1475 cm (NNO)

20

<OL) = + 43.2 <c = 1, DMF)

Example 2 4

  NZ 12 cqh 1 or: ethyl) N 4 lnitrosocarbamoyl L-isoleucine <2-chloro

  ethyl): 13 amide Obtained from the precursor of Example 1 4 Method A Chromatography eluent zdichloromethane / ethyl acetate <3/1)

Recrystallization in the ether.

  Yield: 67% F = 103-104 ° C (dec) Ana lysis CH 2 N 403 C 1 (CN) TLC Rf 0.58 (dichloromethane / ethyl acetate 1/1> -1 IR v = 1480 cm (N-) NO) (C) = 37.2 (c = 1, DMF) <c D

Example 2

  : 12-chloro-ethyl L) N-nitrosocarbamoyl-L-leucine (2-chloroethyl)

  ethyl-14-amide Obtained from the precursor of Example 1 Process A Chromatographic eluent: ethyl acetate / petroleum ether 3/1 Recrystallization from a mixture of ethyl acetate and petroleum ether (1/10) Yield: 71% F = 117 118 C (dec) Analysis * CH 2 N 403 C 12 (CHN) TLC = Rf = O 52 (ethyl acetate / hexane 2/1) IR = V 1430 cm 1 (N-NO) <(a) 20 = + 18.5 (c = 1, DMF) D

Example 2 6

  N, 12-chloro-ethyl) N-nitrosocarbamoyl-L-methionine (2-chloro-ethyl-15-amide) From the precursor of Example 1 6 Method B Chromatographic eluent with ether Recrystallization from a mixture of ether and petroleum ether (1/1) Yield: 63%

Mp: 53-55 ° C

  Analysis: C 1 H 18 N 403 S Cl (C, HN) TLC: Rf = 0.64 ether) IR = v = 1485 cm-1 (N-NO) (20 = + 95 (c = DMF) (a) ) = + 9.5 (c = 1, DMF) D

Example 2 7

  N :( 2-chloroethyl) N-nitrosocarbamoyl sarcosine (2-chloroethyl)

  Ethyl D-16-amide From the precursor of Example 1 7 Method B Chromatography eluent: dichloromethane / ethyl acetate (9-1) Recrystallization from a mixture of ether and hexane (1/1) Yield 63%

F = 63 650C

  Analysis C 8 H 14 N 403 C 12 (C, H, N) IR: V (N-NO) = 1470 cm -1

  Rf = 0.36 (ethyl acetate / dichloromethane

methane 1/1)

Example 2 8

  N, N-Dimitrosocarbamoyl-Lysine-2-chloro-ethyl-17-amide

  From the precursor of Example 1 8.

  Method A modified in that double quantities of DIEA and "activated" nitrosocarbamate are introduced,

  since lysine has two amine functions.

  Chromatography eluent: dichloromethane / ethyl acetate (9/1) Recrystallization from a mixture of ethyl acetate and petroleum ether (1/4) Yield: 52% F = 69 C (dec) Analysis: C 14 H 24 N 507 C 13 (CHN) TLC = Rf 0.40 (ethyl acetate / hexane 1/1)

254 C 49 1

  -1 IR: V = 1470, 1480 cm 1 (N-NO) () = + 12.3 (c = 1, DMF) D

Example 2 9

  2-chloro-ethyl) amide / N- (2-chloroacetic acid)

  ethyl) N-nitrosocarbamoyl-L-18-as Rartigue From the precursor of Example 1 Process A The crude product of the reaction is triturated in water, dried, triturated in ether, dried. obtained is recrystallized in a mixture of acetone and

of hexane (1/1).

Yield: 70% -

  M.p. = 156-157 ° C (dec) Analysis: ## STR13 ## C, Rf = 0.29 (chloroform / ethyl acetate 3/1), IR v = 1475 cm -1 (N. -NO) (a) - + 23.0 (c = 1, DMF) D The compounds of the invention exhibit, like the known nitrosoureas, an oncostatic activity,

  anti-neoplastic and antimitotic.

  These compounds therefore constitute anti-cancer drugs for the treatment of tumors

malignant in humans and animals.

  The oncostatic activity of certain compounds of the invention as compared with other nitrosoureas

  known was determined by following the experimental protocol

  following: F 1 mice (DBA / 2 XC 57 B 1/6) are inoculated with 10 L1210 leukemia cells by

  intraperitoneal route at day 0 and divided into 5 groups.

  The first is the control group and the other four are treated with the test products at different concentrations, on days 1,5 and 9. The compounds are injected in suspension in the oil. Animal mortality is observed and the autopsy indicates if she

  is due to leukemia or the toxic action of the drug.

  The results, for each dose of product, are expressed in T / C (%) (T is the median survival of the treated group and C the median survival of the control group T / C = when 50% of the animals are cured T / C> 125% means

that a drug is active.

  These tests were carried out using compounds of formula Cl-CH 2 -CH 2 N-C -N (R) -A-C X

NO O

  for different amino acids and different

  substituents X (C-terminal substituent).

  The meanings of X are the following: 1) Compounds of the invention: X = -NH-CH 2 -CH 2 Cl, -N (CH 2 -CH 2 -C 1) 2 and -NH-C 6 H 4 N (CH 2 -CH 2 -Cl) 2, 2) Compounds outside the invention: X = -NH 2

and -NH-CH 3.

  The results are shown in the table below. 0.4 do, a 6 X / But at 5 X / Bur Xvm BX / Bur Osla = 1 G Temqdo esoa O le (le ex D / m OS Icr Mifflai D 910 D z Kipm 1 1 X iwrivesin SCID-1, Services

$ 1 1

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09 _ O

p / Umm-prepi o-OT OP-Oz OZ-OT

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TO ?: Ho ZHD-HN-

ZHN- _PT-

TD EHDZHD RN-

úHo-HN 1 z RN- -PT- -PT-, E E

* TO HD HD RN- '

  z (TO? HO ZHD) N_ _PIF_ -PT- -PT- -PT-

TD EHOEHD h N-

  alla ms Ari neu neu net 1 OTI y% "ATE) A-lO us 1 V dsv X VW 5 e W t 1 i AND ZT TT L slz T OE: ZE SET THIS OP 9 ÈET i SZT OTT sz 9 C. OET OOT SE oz v '% 9 EZ oz Oc ST

 T 9% TIZ

  SE OS OP ZT oz SE SE oz Co W 01 r C> _r in tv o 1-1 Co O m oe WWW Co WW (-ddT) ol z 1 1 Seen REINOD gjj Aij Dvt has 2 m saci rivi x The Asp and Lys drifts comprise respectively 2 functions -NH CH 2 CH 2 C 1 and 2 functions-NH-CN-CH 2 CH 2 Cl it NO NO NO N SUBSTITUTE ACID X DL T / CMEDI Optimum dose I = LD 50 AMINE COTE C TERMINAL mg mg / kg mg / kg Opt. 16 Phe -NH 2 55 Maximum T / C = 40 mg / kg 17 Phe -NH-CH 3 38 15-30 22 1.70 18 Phe -NH- ± N (CH 2 CH 2 Cl) 270 Maximum T / C = 173% to 20 mg / kg

I 1

  19 Pro -NH CH 2 CH 2 C 1 80 Maximum T / C = 194% at 35 mg / kg Trp -id 65 2035 27 2.40 21 Tyr -id 40 Maximum T / C = 211% at 25 mg / kg I lo Fi 3 n> p%% O The previous table reports the values LD 50, T / C, MEDI (Effective maximum internal dose = maximum activity plateau corresponding to T / C = a), dose

optimal and therapeutic index.

  The results of the table show that the 2-chloro-ethylamide compounds of the invention are more effective

  than the known amide compounds (-NH 2 C-terminal side).

  Thus, compounds Nos. 9, 13 and 15 are much more effective than compounds N 10, 14 and 16 as shown in the table below. LEU N derivatives C-terminal substituent -9 -NH CHCH 2 Cl MEDI between 15 and 50 mg / kg 2 C 2 mgk S 10 -NH 2 no plateau of maximum activity Derivatives of MET 13 -NH CH 2 CHE 2 CIL MEDI between 10 and 30 mg / kg 14 a ENH 2 no plateau of maximum activity Derivatives of PHE 15 -NH CH 2 CH 2 C 1 MEDI between 40 and 60 mg / kg 16 -NH 2 no plateau of maximum activity I It should also be noted that the LD 50 values show

  that the compounds are not very toxic.

  The invention also relates to pharmaceutical compositions containing as active ingredient a compound

of formula I defined above.

Claims (12)

  Compounds of formula Yf N (R) -AC X (I) O of L, D, DL, allo and threo series, in which: A represents the fragment of an amino acid of formula HN (R) -A- COOH, where R represents a hydrogen atom, an organic radical, in particular an alkyl radical, or forms with the nitrogen atom and has a heterocycle; Y represents a nitrosourea radical of formula O O   C1-CH2-CH2N-C or CH-N-C; and 2 2, C 3 -C, e NO NO   X represents a nitrogen mustard radical of the form of Cl-CH 2 -CH 2 -NH-, (Cl-CH 2 -CH 2) 2 N or (Cl-CH 2 -C 2 -H 2) Compounds according to Claim 1 of foaming Yt-NH-CH-C i X {Ia} 1 il R 'O in which:   R 'is selected from the radicals -H, CH 3, -CH 2 OH, -   -CH-OH, -CH (CH 3) -CH 2 -CH 3 -CH 2 -CH (CH 3) 2   CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 CH 3 CH 2 -CH CH- H OH   2 O-N 2 -2 -2 CONH 2 (CH 2) CO-X- (CH) NU-Y,   CH 2 H -CH-CE-OH - (CH) CH OH-C 2 N   - (CH 3 NH-C-NH-Y, -CH 2 -CH SH, 2H-C   NH n represents an integer of 1 to 7; and   X and Y have the same meaning as in claim 1.   Compounds according to claim 1 of the formula: Y {NH- (CH 2) -1 x (Ib) o 2 -o wherein n represents an integer of 1 to 7; and   X and Y have the same meaning as in claim 1.   Compounds according to claim 1 of formula N -X (Ic) or (Id) Y, Y   in which R represents an organic radical, in particular an alkyl radical   X and Y have the same meaning as in claim 1.   Compounds of formula I according to claim 1, wherein A represents the fragment of an amino acid selected from Ala, B Ala, Asp, Asn, Gly, GABA, Ileg Leu, Lilies, Met, Phe, Pro, Trp and Tyr -   Process for preparing a compound of formula Y N (R) -A-C X (I)   wherein A, X and Y have the meaning given in claim 1, characterized by reacting a compound of formula P fN (R) -AC IO Act (II) oo A has the meaning above, P represents a protective group and Act an activating group, on the hydrochloride de-1-amine of formula HX (III)   X has the above meaning to give a compound of formula P (N (R) -AC x (IV)) that the compound of formula IV is hydrogenated to give a compound of formula NN (R) -Af 3 -J X (V 1 (V)   that the compound of formula (V) is reacted with a nitrosocarbamate of formula Y-O Act (VI)   o Y and Act have the meaning above.   to give the compound of formula I.   The method of claim 6, wherein   characterized by the fact that P is a benzyloxycarbonyl (Z) group or a t-butyloxycarbonyl (Boc) group and Act is   a paranitrophenol or N-hydroxysuccinimide radical.   Process according to one of the claims   6 and 7, characterized in that the reaction of the compound of formula II with the compound of formula III in the presence of an organic solvent is carried out, the solvent is then distilled off, and the residue is taken up. in ethyl acetate, that the resulting organic phase is dried and concentrated, and that recrystallizes the residue obtained.   9 Process according to claim 6, characterized in that the compound of formula IV is hydrogenated in an organic solvent in the presence of palladium on charcoal, the catalyst is removed by filtration and concentrated to dryness and dried the filtrate obtained.   Method according to one of the claims   C 6 and 9, characterized in that the compound of formula V is dissolved in an organic solvent and the nitrosocarbamate of formula VI is added thereto, and the reaction mixture is concentrated under reduced pressure after being left at room temperature. the ambient temperature, which is chromatographed and the residue is recrystallized   the pure compound of formula I thus obtained.   As a medicament particularly suitable for the treatment of tumors, a compound according to one of the Claims 1 to 5.   Pharmaceutical composition containing as active ingredient a compound according to one of the Claims 1 to 5.